Thymic adipogenesis and age-related thymic demise

描述（由申请方提供）：胸腺产生幼稚T细胞的能力随着进行性衰老而降低，这仍然是免疫学的一个基本和令人困惑的现象，迄今为止，这是一种导致老年人免疫功能障碍的难治性临床病症。 随着年龄的增长，胸腺发生显著的纤维化和脂肪化变化，最终转化为脂肪组织。异位脂肪细胞的谱系和胸腺脂肪细胞在衰老过程中的发育机制尚不清楚。 使用谱系追踪，我们的研究小组已经表明，FoxN 1+胸腺上皮细胞（TEC），这是必要的T细胞发育，可以过渡， 产生胸腺脂肪形成前体。 与这种新的范例相一致，我们最近的初步数据提供了进一步的体内证据，即衰老胸腺中的前脂肪形成细胞可以通过次级间充质前体起源于上皮和内皮谱系。基于我们的新发现，该建议的中心假设是，TEC和内皮细胞的过渡有助于胸腺脂肪细胞的谱系，并导致与年龄相关的胸腺退化。 由此推论，阻断TEC和内皮细胞系细胞中的纤维形成和促脂肪形成信号将保护胸腺免受衰老。 目的1中的实验将检验假设1，即随着年龄的增长，FoxN 1+细胞通过上皮-间充质转化（EMT）过程转化为成脂前体，产生异位胸腺脂肪细胞并损害胸腺基质微环境。目的2将检验假设2，即内皮细胞作为脂肪生成祖细胞，并将揭示阻断胸腺血管周围空间异位脂肪细胞的发育可防止胸腺衰老。目的3将检验假设3，即胸腺中与年龄相关的纤维化导致胸腺生成减少，并揭示将次级间充质细胞转化为脂肪细胞的机制参与胸腺功能障碍。 本研究项目的长期目标是了解导致胸腺肥胖的机制，并开发新的方法来预防或逆转与年龄相关的胸腺退化过程。

DESCRIPTION (provided by applicant): Diminished ability of thymus to produce naive T cells with progressive aging remains a fundamental and puzzling phenomenon for immunology and to-date, an intractable clinical condition that contributes to immune dysfunction in elderly. With advancing age, the thymus undergoes striking fibrotic and fatty changes that culminate in its transformation into adipose tissue. The lineage of ectopic adipocytes and the mechanism of development of thymic adipocytes during aging are not well understood. Using lineage-tracing, our research team has shown that FoxN1+ thymic epithelial cells (TECs), that are necessary for T cell development, can transition and give rise to thymic adipogenic precursors. Consistent with this new paradigm, our lates preliminary data provide further in vivo evidence that proadipogenic cells in aging thymus can originate from epithelial and endothelial lineages via a secondary mesenchymal precursor. Based on our novel findings, the central hypothesis of this proposal is that the transition of TECs and endothelial cells contribute towards the lineage of thymic adipocytes and leads to age-related thymic involution. The corollary is that blocking the fibrogenesis and pro- adipogenic signaling in TEC and endothelial lineage cells will protect against aging of thymus. Experiments in Aim 1 will test the hypothesis 1 that with advancing age transition of FoxN1+ cells into adipogenic precursors via epithelial-mesenchymal transition (EMT) process gives rise to ectopic thymic adipocytes and compromises the thymic stromal microenvironment. Aim 2 will test the hypothesis 2 that that endothelial-lineage cells serve as adipogenic progenitors and will reveal that blocking he ectopic adipocyte development in thymic perivascular space protect against thymic aging. The Aim 3 will test the hypothesis 3 that age-related fibrogenesis in thymus causes reduction in thymopoiesis and reveal that mechanisms that commit secondary mesenchymal cells into adipocytes participate in thymic dysfunction. The long-term goal of this research project is to understand the mechanisms that cause thymic adiposity and to develop new approaches to prevent or reverse the process of age-related thymic involution.